The origins and spread of antimalarial drug resistance: Lessons for policy makers
Introduction
Substantial advances have been made in our understanding of the genetic basis of drug resistance in malaria parasites during the past 15 years. We know that specific point mutations in dhfr and dhps underlie resistance to pyrimethamine and sulfadoxine (Cowman et al., 1988, Triglia and Cowman, 1994, Brooks et al., 1994), while point mutations in mitochondrial DNA (mtDNA) underlie resistance to atovaquone (Schwobel et al., 2003). A major locus underlying resistance to chloroquine (CQ) has been characterized and the principal mutations involved identified by fine-scale association mapping and elegant transfection experiments (Cooper et al., 2002, Djimde et al., 2001, Fidock et al., 2000, Sidhu et al., 2002, Waller et al., 2003). A second locus, pfmdr, also contributes to CQ resistance, although it is not essential (Wellems et al., 1990, Foote and Cowman, 1994, Foote et al., 1990, Reed et al., 2000), and both copy number changes and point mutations in this gene also play a role in resistance to mefloquine, halofantrine, quinine and artemisinin derivatives (Barnes et al., 1992, Foote et al., 1989, Pickard et al., 2003, Price et al., 2004).
While we have some information about key polymorphisms underlying drug resistance, much less is understood about the dynamics of resistance gene evolution in parasite populations. Two processes are necessary for evolution of resistance. First, resistance mutations are generated by mutation. Second, these mutations spread within and between parasite populations. Important inferences about the rate of drug resistance mutation can be gleaned from laboratory selection experiments (Paget-McNicol and Saul, 2001, Peters et al., 2000, Cooper et al., 2002, Rathod et al., 1997). However, these experiments cannot provide information on the subsequent survival of resistant mutants in nature. An alternative retrospective approach is to investigate the evolutionary history of drug resistance mutations using molecular markers that are closely linked to resistance alleles. We review recent information about the evolutionary dynamics of drug resistance genes obtained using this approach. We describe available information on the numbers of origins and routes of spread of known resistance genes. We evaluate possible explanations for the patterns observed and we highlight the implications of these data for resistance management. Throughout the manuscript, we identify key areas of research where more work is needed.
Genotyping of molecular markers (single nucleotide polymorphisms (SNPs), microsatellites) situated very close to drug resistance genes provides a powerful approach to determining the numbers of origins of spread of resistance and compliments epidemiological and clinical data describing the emergence of resistance. Since the recombination rate is high in Plasmodium falciparum (Su et al., 1999), markers should be positioned as close as possible to the resistance genes. Markers spaced within 5 kb are ideal though even at this distance recombination may obscure patterns of variation (Anderson, 2004). Non-coding point mutations have the advantage of low mutation rates (∼10−9 per generation) (Drake et al., 1998), but the relative rarity of SNPs in P. falciparum (one every kb; Mu et al., 2002) limits the use of these markers for investigating origins of resistance genes. Coding mutations within genes also provide useful indicators. However, sequence identity at selected codons may provide poor indicators of origins, since convergent evolution may result in identical changes occurring independently. For example, identical codon changes have occurred in pfcrt in South America and Papua New Guinea (Table 1) (Wootton et al., 2002, Mehlotra et al., 2001). Microsatellites provide particularly useful markers, since they are abundant, easily genotyped and have multiple alleles per locus (Ferdig and Su, 2000). We summarize available information obtained about the origins of four known drug resistance genes using this approach.
The discovery of the CQ resistance transporter (pfcrt) was a major triumph for malaria research (Su et al., 1997, Fidock et al., 2000). The long lag time between introduction of CQ and first reports of resistance were consistent with complex changes being needed, while simultaneous appearance of resistance in both SE Asia and South America suggested at least two independent origins (Payne, 1987). There was a 17 years lag between the occurrence of CQ resistance in Asia and its first appearance in east Africa, after which dispersal occurred in a ‘step by step country-to-country systematic progression with little evidence of leapfrogging’ (Payne, 1987). Examination of point mutations in pfcrt and microsatellite sequences close to this gene on chr 7 provide a more detailed picture of resistance evolution. Point mutations in the pfcrt gene demonstrate at least four origins of resistance alleles, including a single origin in SE Asia and Africa, two independent origins in South America and an additional independent origin in Papua New Guinea (Fidock et al., 2000). All alleles conferring CQ resistance have the K76T mutation critical for resistance. Resistant alleles in Asia and Africa have an additional seven to eight amino acid changes, those in South America have four to five other amino acid changes, while those in Papua New Guinea have five changes. Microsatellite data from chr 7 confirm these four independent origins (Wootton et al., 2002) and demonstrate that identical coding changes evolved independently in Papua New Guinea and South America (Mehlotra et al., 2001). Recent sequencing studies suggest one or two additional origins of resistant pfcrt alleles, although microsatellite work is needed to confirm these. Alleles with unique combinations of point mutations have been located in Cambodia (Lim et al., 2003) and the Philippines (Chen et al., 2003). Further surveys may reveal additional origins, but the final count is likely to be between five and eight.
The pfcrt data also provide the direct evidence of the critical role of parasite migration in the spread of resistance alleles. The demise of CQ as a first line treatment in Africa resulted from transfer of resistant alleles from SE Asia (Payne, 1987, Su et al., 1997). More recent studies have demonstrated these same alleles have also spread to South America (Vieira et al., 2004), and to the Philippines (Chen et al., 2003).
Four point mutations in dhfr underlie resistance to pyrimethamine (Plowe et al., 1997). Until recently it was assumed that mutations in dhfr conferring resistance have multiple origins (Doumbo et al., 2000). In particular, the ease with which mutations can be generated in the laboratory (Paget-McNicol and Saul, 2001) and the speed with which resistance appears following initiation of treatment with pyrimethamine (Clyde and Shute, 1957) suggested multiple origins. Three recent molecular studies investigating parasites from three different continents, demonstrate that this model of pyrimethamine resistance evolution is only partially correct (Cortese et al., 2002, Roper et al., 2003, Nair et al., 2003). While all three studies suggest multiple origins of low-level resistance, there are very limited numbers of origins of high-level pyrimethamine resistance (those alleles with ≥3 mutations).
Cortese et al. (2002) examined parasites collected from five countries in South America, by genotyping point mutations in dhfr as well as two microsatellite markers close to this gene. They found multiple microsatellite alleles associated with the alleles bearing the S108N mutation, but only a single two-locus microsatellite haplotype associated the triple mutant. Results from Africa are strikingly similar. Roper et al. (2003) examined single clone infections from both South Africa and Tanzania using three microsatellite markers close to dhfr. They found multiple origins of parasites containing a single mutation (S108N), two separate origins of parasites carrying the double mutant (N51I/S108N) and a single origin of another double mutant (C59R/S108N), and just a single origin of parasites carrying the triple mutant dhfr allele (Fig. 1A). The haplotypes surrounding both the triple and double mutants were the same in both locations, indicating that these alleles have been driven through a broad swath of Africa. Similarly, Nair et al. (2003) examined parasites from 11 populations in Burma, Thailand, Cambodia, Vietnam and Laos, using six di-nucleotide microsatellites within 5 kb of dhfr. As in Africa and South America, alleles containing a single mutation had different flanking microsatellites suggesting multiple origins. However, all alleles carrying two to four mutations had identical or very similar flanking microsatellites indicating a single origin.
These three studies used different microsatellite markers precluding direct comparison between flanking region polymorphisms between the different countries. Roper et al. (2004), therefore, compared parasites from Thailand with two to four mutations with samples from South Africa. These data demonstrate the triple mutant dhfr alleles currently spreading through Africa have identical or very similar flanking regions to those from SE Asia, indicating that these alleles result from import of parasites from SE Asia, while the three double-mutants in Africa have independent origins. Hence, high-level pyrimethamine resistance has followed a strikingly similar path to CQ resistance—a single origin in SE Asia followed by intercontinental spread and invasion in Africa. It is tempting to speculate that both resistant pfcrt and dhfr alleles arrived in Africa in the same parasite genome. SE Asian parasites with high levels of pyrimethamine resistance were abundant in SE Asian countries when CQ resistance first arrived in Africa.
Further surveys are required to see whether the same allelic lineage has reached South America or Papua New Guinea. Such work will reveal how many additional origins of high-level pyrimethamine resistance have occurred. Current data suggest as few as three independent origins of high-level pyrimethamine resistance worldwide. We predict <10 origins for dhfr alleles carrying three to four point mutations.
Four point mutations are involved in dhps resistance and, as with dhfr, these appear sequentially following introduction of treatment with sulfadoxine–pyrimethamine (SP). Information on the origins of dhps alleles comes from two published studies (Roper et al., 2003, Cortese et al., 2002). Both are consistent and suggest very few origins of high-level dhps resistance in the South American and African population samples examined. Cortese et al. (2002) genotyped two microsatellite markers immediately adjacent to dhps on chr 8. As with dhfr, dhps genes containing a single mutation were found on many different microsatellite backgrounds. However, only two different haplotypes were associated with the triple mutant allele. Further microsatellites need to be genotyped to determine whether there have been one or two origins of the triple mutant in this sample set, since one of the markers used shows minimal variation in sensitive parasites. In Africa, the double mutant dhps allele (A437G/K540E) has a single origin (Fig. 1B) and is found on the same genetic background in both South Africa and Tanzania (Roper et al., 2003). Longitudinal data indicate that this double mutant is spreading rapidly through parasites populations, in the wake of the triple mutant dhfr allele. In SE Asia, the situation appears more complex. Microsatellite diversity is reduced around the dhps locus. However, two to three microsatellite haplotypes are found associated with dhps alleles, and recombination and mutation muddy the picture (Anderson, unpublished). However, it seems clear that there have been ≥3 independent origins in SE Asia. Further surveys using common microsatellite markers are required to map the spread of particular resistance alleles and their accompanying flanking regions both within and between continents.
It is now clear that point mutations in pfmdr may influence, but are not essential, for CQ resistance. Similarly, work in the 1990s suggested that copy number amplification plays a major role in resistance to mefloquine, quinine and halofantrine resistance (Barnes et al., 1992, Foote et al., 1989). This work has been strongly supported by recent development of real time PCR assays, which demonstrate strong association between copy number and in vitro resistance to mefloquine (MFQ), quinine (QN) and artemisinin derivatives (Pickard et al., 2003, Price et al., 2004). In addition, this work demonstrates that copy number changes can predict treatment success of these drugs within patients, and may therefore provide a useful molecular markers for mapping resistance (Price et al., 2004).
There is only fragmentary information describing the frequency at which point mutation and copy number amplification occurs in pfmdr. Duraisingh et al. (2000) genotyped a trinucleotide microsatellite within the linker region of pfmdr. They observed significantly lower levels of microsatellite variation in pfmdr alleles containing the N86Y associated with CQ resistance, and suggested that limited numbers of origins and a selective sweep might be responsible for this. A priori we might expect copy number changes to occur more commonly than point mutations, since there is extensive size polymorphism in P. falciparum and the rate of the rate of chromosomal evolution is quite rapid (Corcoran et al., 1986, Sinnis and Wellems, 1988). Three lines of evidence suggest that amplifications involving pfmdr have multiple origins, although the numbers of origins may be quite modest. First, three recent studies in SE Asia have compared point mutations present in amplified and non-amplified pfmdr genes (Price et al., 1999, Price et al., 2004, Pickard et al., 2003). All three studies demonstrate that multicopy pfmdr have two different configurations of point mutations. They may contain wild-type pfmdr alleles or alleles containing the 184F mutation. Mutations in codons 86, 1034, 1042 and 1246 have not been found in amplified copies of pfmdr. Functional constraints have been inferred to explain this relationship; it is conceivable, for example, that amplified copies of pfmdr containing the 1042 mutation present in about 10% of parasites from Thailand carry severe fitness costs, and are selected against (Pickard et al., 2003). However, an alternative and perhaps more plausible explanation is that there have been relatively few origins and hence there is strong association between copy number and point mutations.
Chromosomal size polymorphisms data provide further useful insights into resistance evolution. Gene amplification results from duplication of large fragments of chr 5, rather than amplification of pfmdr alone (Foote et al., 1989). As a consequence multiple genes in addition to pfmdr may be included on the duplicated fragment. Mapping the span of these duplication events provides a powerful approach to characterizing numbers of origins. Triglia et al. (1991) used inverse PCR to identify the amplification breakpoint in the B8 malaria strain from Brazil. They then surveyed 25 other independent parasite clones from worldwide locations to search for the same breakpoint. They found that no other independent parasite lines carried the same breakpoint and concluded from this that multiple origins have occurred. However, this conclusion is perhaps premature as the data are consistent with as few as two amplification events. A second study examined macro-restriction maps of chr 5 in 62 isolates from patients at the Hospital for Tropical Disease in Bangkok (Chaiyaroj et al., 1999). They found just two distinct types of Bgl I restriction patterns in isolates showing mefloquine or halofantrine resistance, one with an amplified region of ∼100 kb, and one with amplified blocks measuring ∼30 kb. If we assume that these represent independent amplification events, these data are consistent with just two separate origins in this Thai population sample. Alternatively, the amplifications could have occurred multiple times using the same breakpoints. Further work using a combination of microsatellite genotyping and mapping of amplified fragments should provide a clearer picture of the dynamics of copy number amplification in pfmdr.
Two points should be clear from the discussion above. First, there are surprisingly few origins of mutations involved in resistance to CQ and antifolates, while the situation with pfmdr is currently less clear. Second, migration and intercontinental transfer of resistance alleles have played critical roles in spread of resistance. In the following sections, we evaluate possible explanations for the observed patterns.
Since mutation rates in the order of 10−9 have been measured in Plasmodium genes (Paget-McNicol and Saul, 2001), and numbers of parasites per infected host may reach 1010–12 (White et al., 1999) we might expect to see 10–1000 origins of point mutations conferring resistance within a single host. Yet, the data summarized above suggest that resistance mutations rather rarely establish within parasite populations. Here, we summarize a number of possible explanations for these patterns. We emphasize that these are not mutually exclusive explanations; all may play a role in the evolution of resistance. Further coverage of this topic is found in Hastings (2004).
One possibility is that the effective population size of parasites within a host is considerably lower than the actual numbers (Fig. 2A). Hence, 1010–12 may be a gross overestimate of the number of parasites that can potentially be transmitted to a new host. This disconnect between actual and effective population size may occur for a number of reasons. First, gametocytes are the only stage that can be transmitted to the mosquito vector. Hence, resistance alleles must be found within parasite lineages that are committed to become gametocytes. Only a small proportion (frequently <1%) of asexual stage parasites are committed to become gametocytes (Taylor and Read, 1997). Hence, while large numbers of mutations may arise, the numbers of gametocytes carrying a mutation will be 10–100-fold lower. Second, malaria parasites undergo antigenic variation to avoid immune destruction. Parasites expressing the predominant var gene, will be targeted for destruction by the immune system and are unlikely to be transmitted. Only mutations occurring in a proliferating cell lineage expressing a recently switched var gene are likely to escape immune surveillance and achieve transmission (Gatton et al., 2004, Gatton et al., 2001, Hastings, 2004). Once again, the consequence is that only a small subset of the total parasite population has the potential to be transmitted and transfer resistant parasites to a second host. Such an explanation might help to explain why resistance appears to evolve most rapidly in semi-immune populations (Snow and Marsh, 2002).
Resistance to both CQ and antifolate drugs involves multiple mutations. For example, in the case of CQ resistance resistant alleles differ from wild-type by four to eight amino acid mutations, while resistant dhfr and dhps alleles differ from wild-type by one to four mutations. It is exceedingly unlikely that multiple mutations occur in the same allele during a single replication. A simpler scenario is that the mutations occur sequentially, with parasites bearing a single mutation spreading through a population, then parasites with two mutations, etc. This process results in sequential bottlenecks in the population of resistant alleles (Cortese et al., 2002, Nair et al., 2003) (Fig. 2B). Flanking marker data provide strong support for this process for dhfr and dhps alleles. All three studies of antifolate resistance evolution found multiple origins of alleles bearing a single dhfr or dhps mutation, with only single origins of alleles bearing ≥3 mutations.
Even if mutations conferring drug resistance arise frequently, they may not be transmitted to a new host if they confer a fitness penalty relative to wild-type parasites. Such mutations may only be transmitted if they are accompanied by compensatory mutations that restore parasite fitness (Levin et al., 1997, Schrag et al., 1997). Since the probability of both drug resistance and compensatory mutations arising simultaneously in the same parasite genome (or on the same parasite lineage) are vanishingly small, resistance mutations may have rather few origins (Fig. 2C).
In support of this argument, there is strong evidence for fitness costs associated with drug resistance alleles. For example, Kublin et al. (2003) describe a rapid decline in frequency of resistance alleles at pfcrt after CQ was abandoned as the first line treatment in Malawi. From these data, we estimate that resistant parasites have a 7–13% fitness disadvantage relative to parasites carrying wild-type alleles (Fig. 3). Similarly, experimental work indicates that mutations in mtDNA conferring resistance to atovaquone and mutations in pfmdr conferring resistance to CQ result in reduced parasite fitness in the absence of drug pressure (Hayward et al., 2005, Peters et al., 2002), while yeast transfected with P. falciparum dhfr alleles carrying the I164L mutation grow slower than yeast transfected with wild-type alleles. Fitness costs have not been measured for parasites bearing multiple copies of pfmdr. However, given that amplified regions of chromosomes may exceed 100 kb in size (Foote et al., 1989, Chaiyaroj et al., 1999) and contain multiple genes, we would expect there to be significant metabolic costs associated with replication, as well as dosage effects resulting from imbalance in protein production from duplicated and single copy genes.
No compensatory mutations have been definitively identified in P. falciparum. However, while the critical functional mutation determining resistance in pfcrt is K76T, many of the additional amino acid mutations observed on resistance alleles are likely to be compensatory, resulting in improved fitness in the absence of drug pressure. We note that these additional mutations fail to completely restore fitness to wild-type levels, since resistant alleles decline in frequency in the absence of drug pressure (Kublin et al., 2003). However, these mutations may restore minimal functionality necessary for parasite survival. In a recombining pathogen, such as P. falciparum, we would expect compensatory mutations to be found within the resistance locus or in close proximity. If compensatory mutations are situated in different parts of the genome from mutations underlying resistance then recombination would rapidly decouple compensatory and resistant mutations.
A striking conclusion emerging from the molecular evolutionary studies described is that resistance genes may spread rapidly within countries and jump between continents. Both CQ resistant pfcrt and high-level dhfr alleles have invaded Africa from SE Asia, while Asian pfcrt alleles have also established in South America. The routes by which these migrants arrive are unknown. For instance, resistant parasites could be transferred between countries in a single step, by an infected air passenger. Alternatively, resistance alleles could have reached Africa by land from SE Asia through the spread of resistant alleles across India and the Middle East. In this section, we evaluate the frequency with which parasites bearing resistant alleles are expected to migrate between continents. We also discuss measurement of selection coefficients responsible for driving resistance genes through parasite populations, and their use in predicting spread of resistance alleles.
Levels of gene flow between populations can be inferred from levels of genetic differentiation at neutral loci using the relationship between FST (a measure of genetic differentiation), migration rate (m) and effective population size (N) (Hartl and Clark, 1997):We have used data from a microsatellite survey of nine globally distributed parasite populations (Anderson et al., 2000) to estimate effective rates of migration between continents. The estimates reflect the numbers of migrant parasites that survive and reproduce rather than simply the number traveling. These data reveal FST = ∼0.1 for comparisons between SE Asian and African populations, giving an estimate of 2.25 effective migrants per generation. Assuming 4–6 generations per year, this suggests 9–14 migrant parasites traveling per year between SE Asia and Africa. If we further assume symmetrical migration, then there will be approximately five to seven migrants arriving in Africa from SE Asia each year. Given that 70% of parasites sampled from Thailand carried the I164L allele at dhfr we would expect three to five dhfr alleles carrying this mutation to enter Africa every year. The method assumes that the populations are at migration–drift equilibrium, which is unlikely to be the case for current P. falciparum populations. The numbers derived should be considered estimates of historical gene flow, but most likely underestimate levels numbers of migrants in the current era of mass transportation.
Direct measures of parasite movement from studies of imported malaria provide an alternative way to assess the scale at which global movement of resistance alleles can occur. Every year approximately 500 million people cross international boundaries, 80 million people travel to malaria endemic countries and 10–30,000 people become infected with malaria and carry malaria infections to their home countries (Ryan and Kain, 2000, Kain and Keystone, 1998). The probabilities of acquiring malaria are highest for visitors to regions with high transmission rates such as Papua New Guinea (20% probability of acquiring malaria per month) or Africa (2% probability). In comparison, travelers to SE Asia, where transmission is geographically patchy and characteristically low (entomological inoculation rate (EIR) < 1), rather rarely get malaria (<0.01% probability per month) (Kain and Keystone, 1998). Equivalent data describing numbers of people traveling between malaria endemic countries are far harder to find: we were unable to estimate the annual volume of human traffic between SE Asian countries and Africa. However, fragmentary data support the assertion of widespread migration of parasite between countries. National surveys in countries in the Persian Gulf, adjacent to Africa, provide some insights. For example, 1293 malaria-infected individuals arriving in Kuwait from endemic countries between 1995 and 1998, including ∼25% from Bangladesh, Thailand and the Philippines (Iqbal et al., 2003). Furthermore, anecdotal data suggest the route of transfer of the SE Asian pfcrt haplotype into the Philippines. A single SE Asian haplotype was found on the Island of Morong, close to the United Nations High Commission for refugees that housed 11–16,000 refugees from SE Asia (Chen et al., 2003).
Hastings and Watkins (2005) present a summary of how factors such as treatment coverage, clonality, intrahost interactions, drug half-life and immunity may influence the spread of resistance alleles. Selection pressure resulting from a combination of these factors determines the rate at which resistance genes spread. Selection coefficients can be estimated by measuring the changes in allele frequencies over time and estimating the proportional difference in survival of parasites bearing different alleles. Such measures allow prediction of future spread of alleles under drug pressure, and can be used to quantify the impact of interventions on the rate of resistance spread. Selection coefficients have been quantified in the field under routine use of sulfadoxine–pyrimethamine. The same resistance allele will behave differently depending on which other resistance alleles are present in the population. Relative fitness of alleles is calculated against the average fitness of the population and hence the fitness of an allele is dependent upon the other alleles with which it is competing. Direct measurements of dhfr and dhps haplotype frequencies were made in KwaZulu/Natal in South Africa 4 year apart. This revealed selection coefficients of 0.05 for the triple and 0.076 for the double mutant dhfr allele. For dhps, selection was considerably stronger with coefficients of ∼0.13 for the double mutant dhps allele (A437G/K540E). Importantly, selection coefficients allow informed prediction about the expected spread of different alleles within parasite populations (Fig. 4).
Neutral gene flow may result in the spread of resistance alleles within countries in the absence of drug selection. This is well illustrated by research from the 1950s describing the evolution of low-level pyrimethamine resistance (presumably due to S108N) in Tanzania. Between 1954 and 1956, 2000–3000 inhabitants of Mkuzi in northeast Tanzania were given weekly pyrimethamine prophylaxis over a period of 18 months. Resistance occurred and despite competition with drug sensitive strains it spread rapidly to people not receiving the treatment living up to 150 miles distant (Clyde and Shute, 1957).
Rapid genotyping methods (Pearce et al., 2003, Kwok, 2000) now make large-scale mapping and monitoring of resistance allele frequencies feasible. This will provide much more detailed information about the rate of spread of resistant alleles within a continent. In addition, genotyping of flanking markers can also be used to monitor the spread of particular invading alleles, such as the triple mutant dhfr (N51I/C59R, S108N) and double mutant dhps allele (A437G/K540E) currently spreading in South and East Africa. Such a system allows the decline of drug efficacy to be predicted well in advance of drug failure.
The information reviewed above is both encouraging and discouraging for those involved in controlling malaria. On a positive note, the finding that alleles conferring high-level resistance to antifolate drugs arise de novo much less frequently than we previously thought is definitely good news. Currently, the major strategy currently being promoted to reduce the rate of resistance evolution is combination therapy using artemisinin derivatives (ACT) (Nosten et al., 2000, Nosten et al., 1998, White et al., 1999). A major argument for use of (ACT) is that each one of the partner drugs is protected against de novo origin of resistance mutations (White, 1999). If high-grade resistance occurs rather rarely even when monotherapy is used, then we might expect ACT to significantly delay the origin of resistance to new drugs.
On the other hand, while ACT directly impedes the origin of new resistance alleles, it does not directly address the problem of migration of resistant alleles between countries and continents. Governments may feel that they have little incentive to replace monotherapy with more costly malaria control policies based on ACT if alleles encoding high-level resistance can migrate from neighboring countries or even from different continents. In order to obtain full benefit from ACT, this approach must be implemented on a large-scale in a coordinated manner. To achieve this will require high levels of international cooperation and commitment, as well as external funding.
We feel that more active preventative measures could be put in place to help stem the tide of parasite migration. Controlling international movement of infectious diseases between countries is admittedly a challenging problem. One way to do this would be to screen or treat passengers entering African countries from other endemic countries. There are practical and ethical difficulties with this policy, but we feel that this approach of screening and treatment may be feasible in some form. After all, the threat of SARs prompted an efficient screening campaign at international borders, which was effective in reducing the range and duration of this epidemic. Importing of drug resistant malaria parasites represents a less immediate problem and one that is less threatening to industrialized countries and has therefore gained less attention. Yet, the human and economic costs of importing drug resistant malaria are likely to be considerably higher and longer lasting than import of a transient SARs epidemic. Policies adopted in Kuwait to reduce imported malaria provide an instructive example of feasible interventions. There were 13,000 imported malaria cases per year after the first gulf war. Immigrants to Kuwait are now screened for malaria infection in their home countries prior to travel to Kuwait, which has significantly reduced the numbers of imported infections to <400 cases per year. We hope this review will stimulate more active discussion of measures that could be taken to reduce the role of parasite migration in the evolution of resistance.
Section snippets
Acknowledgements
We thank NIH and the Wellcome trust for grant support.
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